CN1036013A - The tetrazole compound that antihypercholesterolemic is too high and the preparation of intermediate thereof - Google Patents
The tetrazole compound that antihypercholesterolemic is too high and the preparation of intermediate thereof Download PDFInfo
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Abstract
The formula of the invention provides is
Basic cis or cis (4R, 6S) type compound and its are used to prepare the method for too high dose of antihypercholesterolemic.In the following formula: R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl and suberyl; R
12Be hydrogen, C
1~4Alkyl or metallic cation.
Description
The present invention can provide the method for formula III a and the basic cis new intermediate of III b and preparation formula III a and the basic cis-compound of III b, the R among formula III a and the III b
9, R
10And R
12Definition with hereinafter.Above-claimed cpd can be used for preparing enzyme inhibitors 3-hydroxy-3-methyl
Therefore glutaryl coenzyme A (HMG-COA) reductase enzyme can be used for treating that blood cholesterol is too high, the blood biliprotein is too high and disease such as atherosclerosis.The present invention also provides easy chirality method for preparation HMG-COA reductase inhibitor with its some chiral intermediate.
The invention provides and be used to prepare basic cis intermediate too high dose of antihypercholesterolemic, formula III a and III b.
In the formula:
R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl and suberyl; With
R
12Be hydrogen, C
1~4Alkyl or metallic cation.
The present invention also can be preparation formula I and II antihypercholesterolemic and provides intermediate and method for too high dose except the method that formula III a, III b intermediate and preparation formula III a and III b compound can be provided.
In the formula: R
1And R
4Hydrogen, halogen, C respectively do for oneself
1~4Alkyl, C
1~4Alkoxyl group or trifluoromethyl; R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1~4Alkyl or C
1~4Alkoxyl group; With R be the positively charged ion that hydrogen, hydrolyzable ester groups maybe can generate nontoxic medicinal acceptable salt.
Used " C in this specification sheets and claims
1~4Alkyl ", " C
1~6Alkyl " and " C
1~4Alkoxyl group " these several terms, in literary composition, have in addition the dated person, refer to the alkyl or the alkoxyl group of unbranched or side chain without exception, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl etc.Above-mentioned base should contain 1~4 carbon atom, should contain 1 or 2 carbon atom.Except that having the stipulator in addition in individual cases, used " halogen " this term in this specification sheets and claims, expression chlorine, fluorine, bromine and iodine, and used " halogenide " this term in this specification sheets and claims, the negatively charged ion of expression muriate, bromide and iodide.Used " can generate the positively charged ion of nontoxic medicinal acceptable salt " in this specification sheets and claims, expression non-toxic alkali salt (for example salt of sodium, potassium, calcium and magnesium), ammonium salt, no toxic amine (for example trialkyl amines, dibenzylamine, pyridine, N-methylmorpholine, N-methyl piperidine and be used to generate other amine of carboxylate salt) salt, except that other has the stipulator, used " hydrolyzable ester groups " this term in this specification sheets and claims, be illustrated in physiologically acceptable and hydrolyzable ester group, for example C under the physiological condition
1~6Alkyl, phenmethyl and oxy acid methyl neopentyl.
Concerning the compound of formula I, II, XI and XII, pointed in used structural formula as this specification sheets and claims, the two keys of expression be configured as transconfiguration, i.e. (E); And concerning the compound of formula IV, V, VI, VII, VIII and IX, as pointed in this specification sheets and claim, being configured as of the two keys of expression is trans, cis or anti-, along compound configuration, that is to say, be (E), (Z) when n=0, when n=1 be (E) (E), (Z) (Z), (E) (Z) and (Z) (E).
Therefore because compound of the present invention has two asymmetric carbon atoms, as described in this specification sheets and claims, used intermediate includes enantiomorph formula and two kinds of intermediates of diastereomer formula in the method for preparation formula I and II compound.Formula I and II compound contain two asymmetric centers, thereby can have and respectively be four kinds of possible steric isomers of RR, RS, SR and SS enantiomorph.Specifically, the formula I compound of two unsymmetrical carbons of band hydroxyl has four kinds of possible steric isomers on 3 and 5, by name (3R, 5S), (3S, 5R), (3R, 5R) and (3S, 5S) steric isomer.Used " erythro " this term in present disclosure and claims, and expression (3R, 5S) and (3S, 5R) mixture of two enantiomorphs and " threo form closes the polished whetstone of kitchen emperor's fall chaste tree R, 5R) and (3S, 5S) mixture of two enantiomorphs.(3R, 5S) such monadic symbols represents to contain basically a kind of steric isomer with resembling.The lactone compound of formula II also has two asymmetric carbon atoms on 4 and 6, thus four of gained kinds of steric isomers can be referred to as (4R, 6S), (4S, 6R), (4R, 6R) and (4S, 6S) steric isomer.This term of " trans " lactone used in this specification sheets and claims represents that (4R is 6S) with (4S, 6R) mixture of two enantiomorphs; And this term of " cis " lactone, (4R is 6R) with (4S, 6S) mixture of two enantiomorphs in expression.(4R, 6S) such monadic symbols represents to contain substantially a kind of lactone of enantiomorph with resembling.
The replacement 1 of formula III a described in this specification sheets and the claim and III b, 3-dioxane compound and other similar compound, also suc as formula
Shown in, two asymmetric carbon atoms are arranged on 4 and 6, thus four of gained kinds of steric isomers can be referred to as (4R, 6S), (4S, 6R), (4R, 6R) and (4S, 6S) steric isomer.Used " trans "-1 in this specification sheets and claims, this term of 3-dioxane, expression (4R, 6R) with (4S, the 6S) mixture of two enantiomorphs, and " cis "-1, this term of 3-dioxane, (4R is 6S) with (4S, 6R) mixture of two enantiomorphs in expression.Because accidental and the present invention 1 of the best enantiomorph of formula II lactone compound, the best enantiomorph of 3-dioxane intermediate has identical (4R, 6S) steric isomer title, for fear of producing any possible confusion, other has added " trans " and " cis " these two titles.
In the compound of formula III a and III b, R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl.R preferably
9And R
10Respectively be methyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl.R
12Preferably hydrogen, methyl or metallic cation, particularly lithium cation, the compound of formula III a is cis-isomeride preferably, and the compound of formula III b is cis (4R, 6S) isomer preferably.
The too much compound of anti-high cholesterol of formula I and II can in all sorts of ways and produce and preferably use the basic cis intermediate of formula III a and III b.R in the formula
9, R
10And R
12Definition
Justice is with above-mentioned.Therefore, the invention provides the method for a kind of preparation formula III a and III b intermediate, improving one's methods of a kind of preparation formula I and formula II compound also is provided.
Shown in reaction process Fig. 1.The method of the compound of preparation formula III a and III b is: make the ester reaction of the aldehyde and the etheric acid of formula IV; Make the compound reaction of ketone or ketal and formula VI then; Then to 1 of the formula VII of gained, the 3-dioxane is hydrolyzed; The acid of pulling-off type VIII optionally.
Reaction process Fig. 1
Among reaction process Fig. 1: R
7And R
8Hydrogen, C respectively do for oneself
1~6Alkyl or by 1 or 2 C
1~4Alkyl, halogen, C
1~4The phenyl that alkoxyl group or trifluoromethyl replace arbitrarily; R
11Be hydrolyzable ester group, n is 0 or 1, R
9And R
10Definition with above-mentioned.The aldehyde of the method that the ketone ester of formula V can be familiar with the professional by acetylacetic ester and formula IV is in resembling the inert organic solvents of tetrahydrofuran (THF) and so on, temperature about 0 ℃ to reacting under-78 ℃ and the condition that has the alkali such as sodium hydroxide, lithium diisopropylamine and n-Butyl Lithium to exist approximately, prepared.
The formula IV starting material of n=0 and n=1 are known, or make easily by currently known methods.The formula IV starting material of n=1 can also be by n=0 formula IV compound and triphenyl phosphoranediyl acetaldehyde and so on only the uncommon reagent react of ladder or other technical method of knowing are prepared.The professional and technical personnel should be understood that the relative configuration of single pair of key (n=0) in the formula IV starting material or several pairs of keys (n=1) can be that trans, cis or its are hybrid-type.Each geometrical isomer (E) or relative quantity (Z) can be determined according to the reaction conditions that uses in industrial effective rate of utilization or the preparation.In the cited specific embodiment of this specification sheets, be with mainly containing trans (E) mixture of isomers.The personnel of professional technique should be understood that, even in the whole tandem reaction sequence shown in reaction process Fig. 1, can there be a spot of other isomer to exist, reason is that two keys can be oxidized and be removed in ozonolysis reactions, and is therefore not harsh to the requirement of isomer relative quantity.
By making ketone group reductive method, can make the dihydroxy ester of the ketone ester reduction accepted way of doing sth VI of formula V with the technical reductive agent of knowing.Reduction reaction is preferably carried out with two step Stereoselective reduction methods under the Stereoselective situation, so that the output maximum of the best erythro isomer of formula VI dihydroxy ester.Stereoselective reduction reaction tie up to temperature approximately-70 ℃ under the room temperature with three substituted alkyl borines (preferably boron triethyl or three normal-butyl borines) or alkoxyl group Dialkylborane (preferably methoxyl group diethyl borine or oxyethyl group diethyl borine) (Tetrahedron Letters, 28,155(1987)) carry out.And then with sodium borohydride temperature approximately-50 ℃ to approximately under-78 ℃, such as tetrahydrofuran (THF), ether and 1, make the title complex reduction of generation in the inert organic solvents of 2-glycol dimethyl ether and so on (preferably tetrahydrofuran (THF)).Under the situation that adds or do not add hydrogen peroxide and aqueous solution of buffer agent, add methyl alcohol then and finish reduction reaction.The compound of some formula VI is known, is at United States Patent (USP) the 4th, 248, describes in No. 889 (publication on February 3rd, 1981) and the United States Patent (USP) the 4th, 650, No. 890 (publication on March 17th, 1987).
Formula VII compound can prepare with formula VI compound, method is: make ketone such as 2-acetone, propione, cyclopentanone and pimelinketone in inert organic solvents (for example toluene, benzene or dimethylbenzene), temperature about 20 ℃ under the solvent for use reflux temperature, react having under a small amount of organic acid, mineral acid or resinous acid (for example tosic acid) and the vitriolic situation; With siccative (Na for example
2SO
4, MgSO
4And molecular sieve) at random removes the water of generation, perhaps with Dean-Stark trap or similar devices azeotropic dehydration.The reaction of formula VI compound and ketone also can be carried out under solvent-free situation.In addition, above-mentioned formula VII compound can with such as 2,2-Propanal dimethyl acetal and 1, the ketal of 1-dimethoxy hexanaphthene etc. reacts.
R
12For hydrolyzable ester groups be preferably C
1~4The formula III a compound of alkyl, available method in common makes thiazolinyl be oxidized to aldehyde radical, is prepared by the similar compound of formula VII.Another kind method is: at first make formula VII compound hydrolysis accepted way of doing sth VIII compound with the alkaline water solution, make formula VIII compound oxidation then, to obtain R
12Formula III a compound for hydrogen.A kind of easy especially method for oxidation is to make the compound of formula VII or VIII make an appointment with-50 ℃ to react under making an appointment with-78 ℃ with ozone in temperature in the inert organic solvents such as methyl alcohol, ethyl acetate and methylene dichloride.Whether color that can be shown according to reaction mixture is judged with the reaction of ozone and is finished, and (for example methyl-sulfide and triphenyl phosphine decompose the intermediate ozonide, to obtain needed formula III a aldehyde by adding gentle reductive agent.
(4R, 6S) type aldehyde can be prepared by similar racemic acid by the general method of taking racemic mixture apart (for example fractional crystallization after adding suitable salt-forming group) the most desirable formula III b cis.Can to gained with such as (1S, 2R)-diastereo-isomerism salt mixture that the optically-active salt forming agent of ephedrine and α-Jia Jibianji amine and so on forms separates and the salt of taking apart that will tell transforms accepted way of doing sth III b compound.Salt forming agent preferably (1S, 2R)-ephedrine; Separation method is fractionation crystallization preferably.Take apart and can carry out in inert organic solvents, preferably carry out in hydrocarbon alcohol mixed solvent (for example hexane carbinol mixture), during with this mixed solvent, taking salt apart can crystallize out from solution.If desired, can make the acid of formula III b change into R
12Be the salt of metallic cation, or R
12Be C
1~4The hydrolysis ester group of alkyl.
The general method that the too high compound of best antihypercholesterolemic can be described with this specification sheets in formula I and the II is prepared by the compound of formula III a or III b.This general preparation method is existing the description in the following files: U.S. Patent application the 018th, No. 542 (February 25 1987 date of application) and relevant " part continuation application " U.S. Patent application No. (OT-1888A) (date of application) (, the coexistence application), two application people is John J.wright and Sing-Yuen Sit more than; U.S. Patent application the 018th, No. the (OT-1890A) (date of application) (coexistence application) of No. 558 (February 25 1987 date of application) and relevant " part continuation application " U.S. Patent application, more than two application people be John J.wright, Sing-Yuen Sit, Neelakantan Balasu
b
Manian and Peter J.Brown.The use of formula III a aldehyde is shown in reaction process Fig. 2; The use of formula III b chiral aldehydes is shown in reaction process Fig. 3.
Reaction process Fig. 2
Reaction process Fig. 3
Among reaction process Fig. 2 and 3: R
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10And R
12Definition with above-mentioned; With Z be
R in the formula
13Be C
1~4Alkyl, R
14For by 1 or 2 C
1~4The phenyl that alkyl or chlorine substituent replace or the end replaces, X is bromo, chloro or iodo.
Shi Ⅹ phosphonium salt and formula X phosphonic acid ester have description in this manual, description is also arranged: U.S. Patent application the 018th in the following files, No. the (CT-1890A) (date of application) of No. 558 (February 25 1987 date of application) and P " part continuation application " U.S. Patent application (coexistence application), more than two one of the artificial applicant of application and colleague Sing-Yuen Sit, Neelakantan Balasubramanian and Peter J .Brown.Be intended to make R
12Be C
1~4The formula X compound of the formula XI of alkyl or XII compound respectively with the reaction of formula III a or III b compound, can be such as tetrahydrofuran (THF) and N, in the inert organic solvents of dinethylformamide and so on, under the situation that the highly basic existence that resembles n-Butyl Lithium and so on is arranged and in temperature, make an appointment with under-50 ℃ to about-78 ℃ and carry out.When formula X compound is and R
12For hydrogen or III a or III b compound when reacting, preferably with the two normal highly basic that resemble n-Butyl Lithium and so on.Another kind of alternative method is to make the salt of formula III a or III b compound earlier, then with formula X compound and highly basic processing.Methods such as adding, salify and inner salt preparation for the professional and technical personnel, are known.By well-known method; for example use gentle acid (for example 0.5NHCl and 0.5NHCl are dissolved in and resemble in tetrahydrofuran (THF) and so on inert organic solvents); can easily make the tetrazole compound of formula XI or XII slough protection; elder generation's production I a erythro compound or formula I b (3R; 5S) type compound; the universal method of knowing with the professional and technical personnel makes it to be converted into formula II trans-compound or formula II (4R, 6S) type compound then.
In a desirable embodiment of the present invention, formula III a compound is that structure is
Basic cis-compound.In the formula: R
9And R
10Respectively be C
1~2Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; R
12Be hydrogen, C
1~2Alkyl or metallic cation.
In a preferable embodiment of the present invention, formula III b compound is that structure is
Basic cis (4R, 6S) type compound.In the formula: R
9And R
10Respectively be C
1C
1~2Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; R
12Be hydrogen base, C
1~2Alkyl or metallic cation.
In another desirable embodiment of the present invention, formula VIII compound is that structure is
Basic cis-compound.In the formula: R
7And R
8Hydrogen, C respectively do for oneself
1~6Alkyl or phenyl; R
9And R
10Respectively be C
1~2Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; N is 0 or 1.
In another preferable embodiment of the present invention, formula IX compound is that structure is
Basic cis (4R, 6S) type compound.In the formula: R
7And R
8Hydrogen, C respectively do for oneself
1~6Alkyl or phenyl; R
9And R
10Respectively be C
1~2Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; N is 0 or 1.
On the other hand, the present invention can provide formula to be
Basic cis new intermediate.In the formula: R
1And R
4Hydrogen, halogen, CC respectively do for oneself
1~4Alkyl, C
1~4Alkoxyl group or trifluoromethyl; R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1~4Alkyl or C
1~4Alkoxyl group; R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl and suberyl; R
12Be hydrogen, C
1~4Alkyl or metallic cation.
The present invention provides the basic cis intermediate of formula XI in a desirable embodiment.In the formula: R
1, R
2, R
3, R
4, R
5And R
6Respectively do for oneself hydrogen, fluorine-based, chloro, methyl or methoxy; R
9And R
10Respectively be C
1~2Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; R
12Be hydrogen, C
1~4Alkyl or metallic cation.
The present invention provides formula to be in another desirable embodiment
Basic cis (4R, 6S) type new intermediate.In the formula: R
1And R
4Hydrogen, halogen, C respectively do for oneself
1~4Alkyl, C
1~4Alkoxyl group or trifluoromethyl; R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1~4Alkyl or C
1~4Alkoxyl group; R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl; And R
12Be hydrogen, C
1~4Alkyl or metallic cation.
The present invention provides basic cis (4R, 6S) the type intermediate of formula XII in another preferable embodiment.In the formula: R
1, R
2, R
3, R
4, R
5And R
6Respectively do for oneself hydrogen, fluorine-based, chloro, methyl or methoxy; R
9And R
10Respectively be C
1~2Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; R
12Be hydrogen, C
1~4Alkyl or metallic cation.
Again on the other hand, the invention provides a kind of preparation formula is
The method of basic cis aldehyde.In the formula: R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl; R
12Be hydrogen, C
1~4Alkyl or metallic cation.The step that this method comprises has:
(a) make formula be
Basic erythro dihydroxy thing under the situation that has small amount of acid to exist be with at least 1 equivalent formula
Compound (R in the formula
9And R
10Definition with above-mentioned) reaction, to produce formula be
Compound; In the formula VI: R
7And R
8Hydrogen, C respectively do for oneself
1~6Alkyl or by 1 or 2 C
1~4Alkyl, halogen, C
1~4The phenyl that alkoxyl group or trifluoromethyl replace arbitrarily, R
11Be the hydrolysis ester group, n is 0 or 1; R in the formula VII
7, R
8, R
9, R
10And R
11And the definition of n is with above-mentioned;
(b) at random make the ester hydrolysis of formula VII, to make formula VIII compound
R in the formula
7, R
8, R
9And R
10Definition with above-mentioned;
(c) make formula VII compound or formula VIII compound oxidation, be to produce formula
Basic cis-compound, R in the formula
9, R
10And R
12Definition with above-mentioned.
The present invention provides a kind of preparation formula to be in a desirable embodiment
Basic cis (4R, 6S) method of type aldehyde; In the formula: R
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl; R
12Be hydrogen, C
1~4Alkyl or metallic cation; The step that this method comprises has:
(a) make formula be
Basic erythro dihydroxy compound under the situation that has small amount of acid to exist be with at least 1 equivalent formula
Compound (R in the formula
9And R
10Definition with above-mentioned) reaction, to produce formula be
Compound; In the formula VI, R
7And R
8Hydrogen, C respectively do for oneself
1~6Alkyl or by 1 or 2 C
1~4Alkyl, halogen, C
1~4The phenyl that alkoxyl group or trifluoromethyl replace arbitrarily; R
11Be the hydrolysis ester group, n is 0 or 1; R in the formula VII
7, R
8, R
9, RR
10, R
11With the definition of n with above-mentioned.
(b) make the ester hydrolysis of formula VII, be to produce formula
Compound, R in the formula
7, R
8, R
9, R
10With the definition of n with above-mentioned.
(c) acid of formula VIII is taken apart, be to make formula
Basic cis (4R, 6S) type compound, R in the formula
7, R
8, R
9, R
10With the definition of n with above-mentioned.
(d) make the acid oxidase of formula IX, and at random prepare its ester, be to make formula
Basic cis (4R, 6S) type compound, R in the formula
9, R
10And R
12Definition with above-mentioned.
Again on the other hand, the present invention can provide a kind of preparation formula to be
The method of basic trans-compound; R in the formula
1And R
4Hydrogen, halogen, C respectively do for oneself
1~4Alkyl, C
1~4Alkoxyl group or trifluoromethyl, R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1~4Alkyl or C
1~4Alkoxyl group; The step that this method comprises has:
(a) make formula be
Compound and formula be
The reaction of basic cis-compound, to produce formula be
Basic cis-compound; R in the formula X
1, R
2, R
3, R
4, R
5And R
6Definition with above-mentioned, Z is
R in the formula
13Be C
1~4Alkyl, R
14For by 1 or 2 C
1~4The phenyl that alkyl or chlorine substituent do not replace or replace, X are bromo, chloro or iodo; R among the formula III a
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them and to be cyclopentyl, cyclohexyl or suberyl, R
12Be hydrogen, C
1~4Alkyl or metallic cation; R in the formula XI
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10And R
12Definition with above-mentioned;
(b) make formula XI compound and acid-respons, be to produce formula
Compound, R in the formula
1, R
2, R
3, R
4, R
5, R
6And R
12Definition with above-mentioned;
(c) make R
12Formula I a compound cyclisation for hydrogen to make formula is
Basic trans-compound, R in the formula
1, R
2, R
3, R
4, R
5And R
6Definition with above-mentioned.
The present invention provides a kind of preparation formula to be in a desirable embodiment
Trans substantially (4R, the 6S) method of type compound, R in the formula
1And R
4Hydrogen, halogen, C respectively do for oneself
1~4Alkyl, C
1~4Alkoxyl group or trifluoromethyl, R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1~4Alkyl or C
1~4Alkoxyl group; The step that this method comprises has:
(a) make formula be
Compound and formula be
Basic cis (4R, 6S) type compound reaction with preparation formula is
Basic cis (4R, 6S) compound; R in the formula X
1, R
2, R
3, R
4, R
5Yue
6Definition with above-mentioned, Z is
R in the formula
13Be C
1~4Alkyl, R
14For by 1 or 2 C
1~4The phenyl that alkyl or chlorine substituent do not replace or replace, X are bromo, chloro or iodo; R among the formula III b
9And R
10Respectively be C
1~4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them and to be cyclopentyl, cyclohexyl or suberyl, R
12Be hydrogen, C
1~4Alkyl or metallic cation; R in the formula XII
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10And R
12Definition with above-mentioned;
(b) make formula XII compound and acid-respons, be to produce formula
Compound, R in the formula
1, R
2, R
3, R
4, R
5, R
6And R
12Definition with above-mentioned;
(c) make R
12Formula I b compound cyclisation for hydrogen to make formula is
Trans substantially (4R, 6S) type compound, R in the formula
1, R
2, R
3, R
4, R
5And R
6Definition with above-mentioned.
The biosynthetic restraining effect of acute cholesterol in the mouse body
Under the situation of putting upside down daylighting timetable at (in the morning to 5 dark in afternoon) at 7, keep the normal diet (Purina mouse feed and water do not add restriction) at least 7 days of male wistar mouse (160~200 grams, 2 of every cage mounteds).After jejunitas 15 hours, administration.With the ester of propylene glycol solution, lactone or the test compound of 0.5~1.0 ml water or sodium salt, use the gastric intubation art, at 8 o'clock in the morning compound is fed in the stomach.The vehicle of contrast mouse sumat talem.
Mouse receiving test material 30 minutes afterwards contains (1-with the peritoneal injection art with 0.9 milliliter
14C) the NaCl solution of sodium acetate (1~3mCi/ mmole) 0.9% (by every kg body weight 120uCi liter) injects in the mouse body.After 60 minutes influx time, mouse is killed, take out liver and blood sample.Centrifugation by heparin+EDTA processing blood gets blood plasma (1.0 milliliters) aliquots containig.Get blood plasma aliquots containig and liver homogenate (it is heavy to be equivalent to the wet liver of 0.50 gram) aliquots containig mensuration and have radiolabeled 3-hydroxy sterol.Tell the sterol in the liver sample according to Kates method (" Techniques " part in " Lipidology " book that M.Kates compiles, pp349,360~363, North Holland Publ.Co., Amsterdam, 1972); Make the direct saponification of plasma sample simultaneously, but continue tell the sedimentary sterol of digitonin.With effective corrected liquid flashing counting determining
14C-mark sterol.What calculate all processing animal groups sneaks into liver cholesterol and plasma cholesterol
14The average percent inhibition of C, and with the mean value of the contrast mouse of testing simultaneously relatively.
Therefore, above-mentioned test can provide substances the mouse that medicinal preparation for oral administration is arranged in the inhibition body to be synthesized again the data of cholesterol ability.For example, by test as can be known, the compound of embodiment 13 still all can not produce 50% inhibition dosage (ED to blood plasma ornitrol and to the liver and gall sterol
50), with the mevinolin(Lovastatin that records with similar approach) value equally matched (Alberts etc., Proc.Natl.Acad.Sci, 77,3957~3961(1980)).
Among following all embodiment, all temperature are centigradetemperature.Fusing point is represented with T Thomas-Hoover capillary melting point apparatus, not correction up.Proton resonance (
1HNMR) spectrum is represented with Bruker AM300, Bruker WM360 or Varian T-60 CW spectrometer.Except that other had dated person, all wave spectrums all were at CDCl
3, DMSO-d
6Or D
2Record among the O and chemical shift all is with δ (from interior mark tetramethylsilane (TMS) to unit that downfield moves) expression.The inner proton coupling constant represents that with hertz (Hz) suggestion of splitting the used symbol of sub-model is as follows: S represents unimodal; D represents doublet; T represents triplet; Q represents quartet; M represents multiplet; Br represents broad peak; Dd represents the doublet (doublet of doublet) in the doublet; Dq represents the doublet (doublet of quartet) in the quartet.13C nuclear magnetic resonance (
13CNMR) spectrum is represented with Bruker AM 300 or Bruker WM 360 spectrometers, is the broad band proton-decoupled.Except that deuterium lock peak person in being marked with, all wave spectrums all are at CDCl
3, DMSO-d
6Or D
2Measure among the O.Chemical shift is with δ (from tetramethylsilane to unit that downfield moves) expression.Infrared (IR) spectrum is with 4000 centimetres
-1To 400 centimetres
-1Nicolet MX-1 FT spectrometer measure, be calibrated to 1601 centimetres of the absorbing wavelength of polystyrene film
-1, with centimetre inverse (centimetre
-1) expression.Relative intensity is expressed as: s represents by force; M represents medium; A little less than representing with w.Opticity (α)
25 DBe the CHCl under normality
3In record with Perkin-Elmer 241 polarimeters.
Analyze thin layer spectrometry (TLC) by precoating silica-gel plate (60F=254) and range estimation realization, use UV-light, iodine vapor and (or) with following a kind of reagent dyeing and heating.Described reagent is: (a) first or second phospho-molybdic acid (2%); (b) reagent (a) is added 5 moles of H of 2% rose vitriol
2SO
4Solution and heating.Column chromatography (also claiming the flash distillation column chromatography) is that (glass column of 32~63 microns silica gel-H) is operated under the air pressure of a little higher than designated solvent with pulverizing silica gel.Ozonolysis reactions carries out with Welsbach T-23 ozonometer.All gasifications of solvent all under reduced pressure realize.Used " hexane class " this term in the specification sheets, as American Chemical Society defined, be meant isomery C
6The mixture of hydrocarbon; This term of 'inertia' atmosphere except that other has dated person, all refers to argon gas atmosphere or nitrogen atmosphere.
Embodiment 1
Cis 2,2-dimethyl-6-(2-phenyl vinyl)-1,3-dioxane-4-methyl acetate
3,5-dihydroxyl-7 phenyl-6-heptenoic acid methyl esters (98% non-enantiomeric purity) (2.37 grams, 9.48 mmoles) and 2, the 2-dimethoxy is that the tosic acid of alkane (20 milliliters) and catalytic amount lumps together stirring 16 hours.Gained solution is distributed between diethyl ether and the dilute aqueous solution of sodium bicarbonate.Under reduced pressure the organic layer drying (is used Na
2SO
4) and concentrate, produce a yellow solid.From isopropyl ether, after the recrystallize, obtain 1.70 gram (62%) title compounds.This compound is a white solid, 84~86.5 ℃ of fusing points.
Another kind of alternative method is, 0.2 gram solid sodium carbonate can be added to 2, in the 2-Propanal dimethyl acetal solution, stirs fiercely then.Leach solid by groove line filter paper.It is unnecessary 2 under reduced pressure to remove, and the 2-Propanal dimethyl acetal obtains a yellow solid.This solid is placed on recrystallize in the isopropyl ether.
1H NMR(CDCl
3)δ:7.37~7.19(5H,m),6.59(1H,d,J=15.9Hz),6.14(1H, dd,J=1.59,6.4Hz),4.57~4.35(1H,m),4.42~4.35(1H,m),3.68(3H,S),2.58(1H,d,J=15.6、6.9Hz),2.14(1H,dd,J=15.6,6.3Hz),1.74~1.61(1H,m),1.52(3H,S),1.43(3H,S),1.45~1.35(1H,m)。
Analyze:
C
17H
22O
4Calculated value: C, 70.32; H, 7.63;
Measured value: C, 70.24; H, 7.69.
Embodiment 2
Cis 2,2-dimethyl-6-(2-phenyl vinyl)-1,3-dioxane-4-acetate
2,2-dimethyl-6-(2-phenyl vinyl)-1,3-dioxane-4-methyl acetate (8.5 grams, 29.3 mmoles) and 1N NaOH(32 milliliter) solution and methyl alcohol (64 milliliters) is heated to backflow, kept 45 minutes.Behind the reduction vaporization, with the diethyl ether wash water solution once, and with the acidifying of 1N HCl33 milliliter.The collecting precipitation thing, and make recrystallize in ethyl acetate/isopropyl ether, get 7.2 gram (90%) title compounds.This compound is a colorless solid, 153~155 ℃ of fusing points.
1H NMR(CDCl
3)δ:7.37~7.20(5H,m),6.60(1H,d,J=16.0Hz),6.14(1H,dd,J=16.0、6.4Hz),4.59~4.54(1H,m),4.43~4.35(1H,m),2.62(1H,dd,J=16.0、7.2Hz),2.51(1H,dd,J=16.0、5.3Hz),1.77~1.72(1H,m), 1.54(3H,S),1.46(3H,S),1.50~1.36(1H,m)。
Analyze:
C
16H
20O
4Calculated value: C, 69.54; H, 7.30;
Measured value: C, 69.20; H, 7.33.
Embodiment 3
Cis 2,2-dimethyl-6-(2-phenyl vinyl)-1, the taking apart of 3-dioxane-4-acetate
The racemize cis 2 of embodiment 2 preparations, 2-dimethyl-6-(2 phenyl vinyl)-1,3-dioxane-4-acetate (0.31 gram, 1.1 mmoles) is dissolved in and contains (1S, 2R)-hexane/ethanol boiling solution of ephedrine (0.2 gram, 1.1 mmoles) in.Make the solution of gained drop to room temperature, obtaining 0.21 gram (41.4%) fusing point is 170~171 ℃ colourless chirality salt very slowly.The pure crystal seed of non-mapping is used in suggestion in unpack procedure.
By acidity processing (as described in embodiment 4) chiral acid that dissociates, by make chiral solvent with L-phenyl trifluoromethyl methyl alcohol
1The enantiomeric purity that H NMR records this chiral acid is 100%, (α)
25 D=+5.45 ° of (C=1, CHCl
3).
Embodiment 4
Cis (4R, 6S)-2,2-dimethyl-6-formyl-1,3 dioxane-4-acetate
The cis 2 of embodiment 3 preparations, 2-dimethyl-6-(2-phenyl vinyl)-1, between 3-dioxane-4-acetate and (1S, 2R)-salt of taking apart of ephedrine (6.6 gram, 14.9 mmoles) (embodiment 3 systems) is distributed in 0.5N HCl(30 milliliter) and the ether.Ether layer is through salt water washing, drying (MgSO
4/ Na
2SO
4) and concentrating under reduced pressure after, 4.1 the gram (99.6%) free acids.This acid is dissolved in the dry dichloromethane (100 milliliters), and passes through this solution down at-78 ℃, till reaching avy blue with ozone.Remove redundant ozone with nitrogen purge method, by adding CH
3SCH
3(5 milliliters) and make solution be heated to room temperature decompose the ozonide of generation, leave standstill then 16 hours.Under reduced pressure concentrate this solution, resistates is dissolved in the isoamyl oxide (about 100 milliliters).Remove the phenyl aldehyde that forms in the ozone decomposition course, under reduced pressure with behind the component distillation of isoamyl oxide obtain title compound.
1H NMR(CDCl
3)δ:9.57(1H,S),4.40~4.30(2H,m),2.60(1H,dd,J=16.0、7.0Hz),2.49(1H,dd,J=16.0、6.0Hz),1.88~1.83(1H,m),1.49(3H,S),1.46(3H,S),1.42~1.31(1H,m)。
Embodiment 5
(3, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-2-propylene-1-yl) dimethyl phosphonate
3, two (4-fluorophenyl)-1-bromo-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-2-propane (1.17 grams, 3.0 mmoles) and both slurries of trimethyl phosphite (0.41 gram, 3.3 mmoles) heated 5 minutes at 100 ℃.Behind the cool to room temperature, remove unnecessary trimethyl phosphite in a vacuum, get a faint yellow solid.This solid is recrystallize in the mixture of ethyl acetate/hexane, obtains lily, fusing point and be 140~141 ℃ solid title compound.
IR(KBr) γ max:1604,1511 centimetres
-1;
1H NMR(CDCl
3)δ:7.7~6.8(8H,m),3.6(3H,S),3.5(3H,S),3.42(3H,S),3.2(2H,d)。
Analyze: N, 13.33
C
19H
19F
2O
3N
4The calculated value of P: C, 54.29; H, 4.56;
Measured value: C, 53.83; H, 4.48; N, 13.50.
Embodiment 6
Cis (4R, 6S)-6-(4, the 4(4-fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazolium-5-base-)-the 1,3-butadiene base)-2,2-dimethyl-1,3 dioxane-4-acetate
The thick chiral acid that embodiment 4 is made is dissolved in the exsiccant tetrahydrofuran (THF) (THF) (50 milliliters), and the solution of gained is transferred in 250 milliliters of three-necked flasks crossing with nitrogen purging, mechanical stirrer is housed thus then.This solution splashes into n-Butyl Lithium (2.5 moles hexane solution, 5.96 milliliters) through vigorous stirring and being cooled to after-78 ℃.Be added near last, solution is transformed into the suspension of the similar solid gel of white.
With fill under nitrogen atmosphere 3, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-and 2-propylene-1-yl) dimethyl phosphonate (6.2 grams, 14.7 mmole) (embodiment 5 system) and THF(50 milliliter) another flask be cooled to-78 ℃, splash into n-Butyl Lithium (2.5 rub hexane solution, 5.96 milliliters) at leisure.The brown-red solution of gained stirred 15 minutes down at-78 ℃.The phosphonic acids anion solutions is transferred to above-mentioned in-78 ℃ of following vigorous stirring suspension that cross, that contain the chiral acid lithium salts by transfer pipet (double ended needle).After adding, the brown solution that gets was thus stirred 30 minutes at room temperature 16 hours then down at-78 ℃.THF solution is distributed between 0.5N HCl and the ethyl acetate.Organic phase salt solution (2 times) washing, dry (Na
2SO
4) and concentrating under reduced pressure.(66: 33: 1/ ether: hexane: after acetate) chromatography purified, (overall yield that is made by the raw material ephedrine salt was 51.6% to resistates to obtain 3.80 grams through silica gel; With the remaining acetate of methylbenzene azeotropic fractionation) yellow spongy title compound.〔α〕
25 D=+106.1°(C=2.23,CHCl
3)。
1H NMR(CDCl
3)δ:7.24~6.82(8H,m),6.62(1H,d,J=15.0Hz),5.32(1H,dd,J=15.0,5.7Hz),4.42~4.37(1H,m),4.30~4.23(1H,m),3.51(3H,S),2.53(1H,dd,J=15.9、7.0Hz),2.42(1H,dd,J=15.9、5.6Hz),1.62~1.57(1H,m),1.46(3H,S),1.33(3H,S),1.30~1.20(1H,m)。
Embodiment 7
Trans-(4R, 6S)-6-(4, two (4-the fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazoliums of 4--5-yl)-1,3-butadiene base)-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one
Cis (4R, 6S)-6-(4, two (4-the fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazoliums of 4--5-yl)-1, the 3-butadienyl)-2,2-dimethyl-1,3-dioxane-4-acetate (3.7 gram, 7.45 mmoles are dissolved in the THF(90 milliliter) and 0.2N HCl(60 milliliter) solution in, left standstill then 16 hours.This solution is distributed between ethyl acetate and the water.Organic layer salt solution (2 times) washing, dry (Na
2SO
4) and concentrating under reduced pressure, resistates is dissolved in the exsiccant methylene dichloride (60 milliliters), 1-cyclohexyl-3-(2-morpholinyl methyl is being arranged) stirred 4 hours under carbodiimide N-first p-toluenesulfonic esters (6.6 grams, the 15.6 mmoles) situation about existing.This solution decompression concentrates, and resistates is distributed between ethyl acetate and the water.Organic layer drying (Na
2SO
4) and concentrating under reduced pressure.(1: 1/ ethyl acetate: ether) chromatography purifies with silica gel.After recrystallize came out from ethyl acetate-hexane, obtaining 1.33 gram (40.1%) fusing points was 172~173 ℃ white solid title compound.〔α〕
25 D=+237.8°(C=2.17,CHCl
3)。
Embodiment 8
3-hydroxyl-5-oxo-6,8-decadienoic acid methyl esters
Diisopropylaminoethyl lithium (476 milliliters, 1.5 moles cyclohexane solution, 714 mmoles) is added to methyl acetoacetate (41.5 gram, 357 mmoles) and THF(500 milliliter) in both cold (30 ℃) solution.Stirred this solution 15 minutes down at-30 ℃.After being cooled to-78 ℃, add 2, the 4-sorbic aldehyde stirred this solution 10 minutes down at-78 ℃, at room temperature stirred then 16 hours.This solution decompression is concentrated, and remaining distribution of slurry is between 1N HCl and ethyl acetate, and organic layer usefulness salt solution (2 times) washs, dry (Na
2SO
4) and concentrate.(ether: hexane/2: 1) chromatography purifies residuum, obtains 18.5 gram (24.4%) oily title compounds with silica gel.
For (E) (E) isomer
1H NMR(200MHz, CDCl
3) δ: 6.3(1H, dd, J=14.7,11.9Hz), 6.02(1H, dd, J=14.7,11.9Hz), 5.75(1H, dq, J=14.7,6.4Hz), 5.5(1H, dd, J=18.7,6.4Hz), 4.74~4.5(1H, m), 3.73(3H, S), 3.51(2H, S), 2.6(2H, d, J=5.8Hz), 1.77(3H, d, J=6.4Hz).
Embodiment 9
3,5-dihydroxyl-6,8-decadienoic acid methyl esters
With boron triethyl (1 mole THF solution, 113 milliliters, 113 mmoles) be added to 3-hydroxyl-5-oxo-6, (18.5 restrain 8-decadienoic acid methyl esters, 86.9 mmole) be dissolved in the THF(300 milliliter) cold (15 ℃) solution in, stirred this solution 20 minutes.This mixture is cooled to after-78 ℃, adds NaBH
4(6 grams, 159 mmoles) and methyl alcohol (37.5 milliliters).This solution of-78 ℃ of following vigorous stirring 30 minutes with at room temperature stirred 3 hours.Decompression is distributed in resistates between 1N HCl and the ethyl acetate after removing down and desolvating.Organic layer drying (Na
2SO
4) and concentrate after, (ether: hexane/3: 1) chromatography purifies residuum, obtains 7.95 gram (42.7%) yellow oily title compounds with silica gel.
For (E) (E) isomer
1H NMR(360MHz, CDCl
3) δ: 6.18(1H, dd, J=15.1,10.4Hz), 6.00(1H, dd, J=15.1,10.4Hz), 5.69(1H, dq, J=15.1,7.0Hz), 5.52(1H, dd, J=15.1,6.7Hz), 4.46~4.37(1H, m), 4.29~4.22(1H, m), 3.69(3H, S), 2.60~2.42(2H, m), 1.72(3H, d, J=7.0Hz), 1.74~1.57(2H, m).
Embodiment 10
Cis 4-(1,3-pentadienyl-1,5-dioxo spiro (5,5) undecane-2-methyl acetate
3,5-dihydroxyl-6,8-decadienoic acid methyl esters (7.6 grams, 35.5 mmoles) and tosic acid (0.1 gram) are added to pimelinketone (10 grams, 100 mmoles), at room temperature stir 16 hours.The yellow solution of gained directly installs on the silicagel column, with ether and hexane (1: 4) eluted product.Suitable cut is merged, obtain the colorless oil title compound of 3.52 grams (33.6%).
For (E) (E) isomer
1H NMR(360MHz, CDCl
3) δ: 6.16(1H, dd, J=15.1,10.6Hz), 6.00(1H, dd, J=15.1,10.6Hz), 5.71~5.65(1H, dd, J=15.1,6.5Hz), 5.47(1H, dd, J=15.1,6.4HHz), 4.44~4.39(1H, m), 4.35~4.30(1H, m), 3.66(3H, S), 2.52(1H, dd, J=1.54,7.9Hz), 2.3(1H, dd, J=15.4,6.5Hz), 2.1~1.18(12H, m), 1.72(3H, d, J=6.5Hz).
Analyze:
C
17H
26O
4Calculated value: C, 69.36; H, 8.90;
Measured value: C, 69.59; H, 9.16.
Embodiment 11
Cis 4-(1, the 3-pentadienyl)-1,5-dioxo spiro (5.5) undecane-2-acetate
Heating 4-(1,3-pentadienyl)-1,5-dioxo spiro (5.5) undecane-2-methyl acetate (3.5 gram, 12.4 mmoles) makes the milliliter at 1N NaOH(13) and both solution of methyl alcohol (26 milliliters) in reflux.After methyl alcohol is removed in decompression,, use ether extraction then with 1N HCl acidifying remainder water solution.Organic layer drying (Na
2SO
4) and concentrate after, residual solid recrystallize from ethyl acetate/hexane comes out, and obtains 2.0 gram (55.9%) fusing points and be 144~146.5 ℃ colorless solid shape title compound.
1H NMR(360MHz,CDCl
3)δ:6.18(1H,dd,J=18.0,12.5Hz),5.72(1H,dq, J=18.0、7.7Hz),5.99(1H,dd,J=18.0、12.5Hz),5.48(1H,dd,J=18.0、7.6Hz),4.45~4.37(1H,m),4.37~4.25(1H,m),2.56(1H,dd,J=18.9、8.8Hz),2.48(1H,dd,J=18.9、6.1Hz),2.60~1.30(12H,m),1.73(3H,d,J=7.7Hz)。
Analyze:
C
16H
24O
4Calculated value: C, 68.54; H, 8.62;
Measured value: C, 68.36; H, 8.55.
Embodiment 12
Cis 4-(4, two (4-the fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazoliums of 4--5-yl)-1,3-butadiene base)-1,5-dioxo spiro (5.5) undecane-2-acetate
A.4-formyl radical 1,5-dioxo spiro (5.5) undecane-2-acetate
Make ozone pass through-78 ℃ 4-(1,3-pentadiene)-1,5-dioxo spiro (5.5) undecane-2-acetate (570 milligrams, 2.0 mmoles) is dissolved in the solution of methylene dichloride (25 milliliters).Solution reaches after the blue look, makes nitrogen pass through solution, removes redundant ozone.Add methyl-sulfide (0.5 milliliter), decompression concentrated solution can obtain sticking buttery title compound.This compound does not need further purification, can use in subsequent processing.
1H NMR(60MHz,CDCl
3)δ:9.57(1H,S),4.52~4.14(2H,m),2.60~2.31(2H,m),2.10~1.10(12H,m)。
B. cis 4-(4, two (4-the fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazoliums of 4--5-yl)-1,3-butadiene base)-1,5-dioxo spiro (5.5) undecane-2-acid
(1.6 milliliters of n-Butyl Lithiums, 4 mmoles, 2.5 the hexane solution of mole) be added to (3, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-2-propenyl of-78 ℃) dimethyl phosphonate (1.7 grams, 4 mmoles) is dissolved in the THF(20 milliliter) solution in.The red tan solution of gained stirred 30 minutes down at-78 ℃.With transfer pipet this solution is transferred to and to be contained 4-formyl-1,5-dioxo spiro (5.5) undecane-2-acetate (steps A system) and THF(10 milliliter) solution in, and maintain-78 ℃.After having shifted, the reaction mixture that combines stirred 1 hour down at-78 ℃, stirred 4 hours under the room temperature.Then this solution is distributed in 0.5N HCl and the cloudy Block of suitable Mei the Huanshui River S thank Wen ether drone time) wash, drying (Na
2SO
4) and concentrating under reduced pressure after, (ether: hexane: acetate/50: 20: 1) chromatography purifies resistates, obtains 342 milligrams of (31.9% overall yield) yellow spongiform title compounds with silica gel.
1H NMR(360MHz,CDCl
3)δ:7.25~6.84(8H,m),6.66(1H,d,J=16.0Hz),5.32(1H,dd,J=16.0,5.10Hz),4.45~4.25(2H,m),3.52(3H,S),2.56(1H,dd,J=16.0、7.6Hz),2.44(1H,dd,J=16.0、5.1Hz),1.89~1.17(12H,m)。
Embodiment 13
Trans 6-(4, two (4-the fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazoliums of 4--5-yl)-1,3-butadiene base)-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one
Make 4-(4, two (4-the fluorophenyl)-3-(1-methyl isophthalic acid H-tetrazoliums of 4--5-yl)-1, the 3-butadienyl)-1, (280 milligrams of 5-dioxo spiro (5.5) undecanes-2-acetate, 0.52 mmole) with 20 milliliters of THF/0.5N HCl(1: mixture 1), kept at room temperature 26 hours.This solution is distributed between salt solution and the ethyl acetate.Organic layer salt solution (2 times) washing, dry (Na
2SO
4) and concentrate after, the sponge of gained (126 milligrams) is dissolved in the exsiccant methylene dichloride (10 milliliters), with 1-cyclohexyl-3-(2-morpholinyl methyl) carbodiimide N-first p-toluenesulfonic esters (0.24 gram) handles.After at room temperature 16 hours, solution decompression evaporation is made eluent with ethyl acetate, and the silica gel chromatography purification residue obtains the colorless oil cut of 38 milligrams of (16.6%) title things, and this cut is the racemic mixture of embodiment 7 compounds.
Embodiment 14
2,2-dimethyl-6-formyl radical-1,3-dioxane-4-methyl acetate
Cis-2,2-dimethyl-6-(2-phenyl vinyl)-1,3-dioxane-4-methyl acetate (embodiment 1 system) is dissolved in the methyl alcohol (10 milliliters), and makes ozone pass through-78 ℃ solution, till the color of solution becomes blue look.Nitrogen is blown over reaction mixture, removes redundant ozone, adds methyl-sulfide then, and heating makes temperature reach room temperature.The vaporising under vacuum reactant, and purify remaining oily matter with silica gel chromatography (the ether hexane with 3: 1 is made eluent), generate title compound.
1H NMR(360MHz,CDCl
3)δ:9.53(1H,S),4.40~4.23(2H,m),3.69(3H,S),2.53(1H,dd,J=15.8、7.02Hz),2.37(1H,dd,J=15.8、5.98Hz),1.85~1.76(1H,m),1.44(3H,S),1.40(3H,S),1.35~1.23(1H,m)。
Embodiment 15
3, two (4-the fluorophenyl)-1-bromo-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-the 2-propylene
A.5-ethyl-1-methyl isophthalic acid H-tetrazolium
2.5 the hexane solution (20 milliliters, 0.05 mole) of mole n-Butyl Lithium is added to 1 under-78 ℃ and the inert atmosphere in 15 minutes time, in 5-dimethyl tetrazolium (4.9 grams, 0.05 mole) and both slurries of exsiccant tetrahydrofuran (THF) (50 milliliters).Stir this mixture 30 minutes, and had flaxen precipitation to form during this period.Then, in 15 minutes time, add methyl-iodide (3.7 milliliters, 0.06 mole).Behind the restir 30 minutes, this transparent reaction mixture of dilute with water uses ethyl acetate (3 * 50 milliliters) to extract then.With chloroform (2 * 25 milliliters) washing waterbearing stratum, the organic layer dried over sodium sulfate of merging, concentrating under reduced pressure obtains a kind of oily matter.Purify this oily matter with distillating method, obtain 5.2 gram (92%) title compounds.The boiling point of this compound under 0.05 mmhg is 89~90 ℃.
1H NMR(CDCl
3)δ:4.05(S,3H),2.86(q,2H),1.41(t,3H);
13C NMR(CDCl
3)δ:156.0、33.24、16.75、11.20。
B.1, propyl alcohol two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 1--5-yl)
(20 milliliters of the hexane solutions of 2.5 moles of n-Butyl Lithiums, 0.05 mole) in 5 minutes, be added in the solution of 5-ethyl-1-methyl isophthalic acid H-tetrazolium (5.6 restrain 0.05 mole) (steps A system) under-78 ℃ (bathe temperature) and the inert atmosphere and 60 milliliters of dry tetrahydrofuran.Mixture stirred 30 minutes, in 5 minutes, add 4,4 '-difluoro benzophenone (10.8 grams, 0.5 mole) is dissolved in the solution of 25 milliliters of dry tetrahydrofuran.This mixture of restir 2 hours will be bathed temperature simultaneously and be brought up to-20 ℃ at leisure.Suppress this reaction with 1N HCl, use ethyl acetate (3 * 50 milliliters) and chloroform (3 * 50 milliliters) to extract then.The organic layer dried over sodium sulfate that merges behind the concentrating under reduced pressure, obtains a white solid.The purging by crystallization in ethanol-hexane of this solid, obtaining 10.8 gram (65%) fusing points is 160~161 ℃ title compound.
IR(KBr) γ
Maximum: 3400 centimetres
-1;
1H NMR(CDCl
3)δ:7.8~7.02(m,8H),5.95(S,1H),4.65(q,1H),3.98(S,3H)1.29(d,2H)。
13C NMR(CDCl
3)δ:162.57、162.37、159.14、156.71、142.48、140.54、128.25、128.13、127.52、127.42、114.67、114.41、114.38、78.56、36.99、33.43、14.52。
Analyze:
C
17H
16F
2N
4The calculated value of O: C, 61.81; H, 4.88, N, 16.96;
Measured value: C, 61.79; H, 4.90; N, 17.09.
C.1, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 1--5-yl)-the 1-propylene
With 1, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 1--5-yl) propyl alcohol (8.25 grams, 0.025 mole) slurries made of (step B system) and 100 milligrams of tosic acid monohydrates and dimethylbenzene (60 milliliters) are heated to backflow, under the situation with Dean-Rodney Stark water storage device, kept 12 hours.In heating, with 1N NaOH(10 milliliter) the washing reaction mixture.Water (100 milliliters) washing then, the spissated product of organic layer is a kind of linen crystal, purify through recrystallize in ethanol-hexane, 7.1 gram (91%) fusing points are 146~147 ℃ white crystals shape title compound.
IR(KBr) γ
Maximum: 1575,1500 centimetres
-1
1H NMR(CDCl
3)δ:7.42~6.85(m,8H),3.53(S,3H),2.14(S,3H),
13CC NMR(CDCl
3)δ:163.37、163.08、160.13、155.61、144.60、145.34、136.47、136.42、136.24、136.19、131.65、131.54、131.11、131.01、119.53、115.51、115.27、115.22、33.50、21.20。
Analyze:
C
17H
14F
2N
4Calculated value: C, 65.37; H, 4.51; N, 17.94;
Measured value: C, 65.64; H, 4.61; N, 18.09.
D.3, two (4-the fluorophenyl)-1-bromo-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-the 2-propylene
With 1, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 1--5-yl)-1-propylene (61.46 grams, 0.197 (step C system), N-bromine succinimide (35.06 grams mole), 0.197 mole) and the slurries made of the Diisopropyl azodicarboxylate of catalytic amount or benzoyl peroxide and tetracol phenixin (1.2 liters) in inert atmosphere, be heated to backflow, kept 2 hours.Make the reaction mixture cool to room temperature, from reactant, leach solid.Filtrate decompression concentrates solid recrystallize in toluene-hexane of gained, obtains 72 gram (93%) fusing points and be 159~160 ℃ white crystals shape title compound.
IR(KBr) γ
Maximum: 1600 centimetres
-1
1H NMR(CDCl
3)δ:7.5~7.1(m,8H),4.44(S,2H),3.53(S,3H)。
13C NMR(CDCl
3)δ:163.94、163.74、160.60、160.45、143.42、149.68、135.20、135.15、134.69、131.43、131.31、130.90、130.80、119.57、115.94、115.77、115.65、115.50。
Analyze:
C
17H
13F
2BrN
4Calculated value: C, 52.19; H, 3.34; N, 14.32;
Measured value: C, 52.58; H, 3.47; N, 14.49.
Embodiment 16
Bromination (1, two (4-the fluorophenyl)-2-(1-methyl isophthalic acid H-tetrazoliums of 1--5-yl)-1-propylene-3-yl) triphenyl phosphonium
With 3, two (4-the fluorophenyl)-1-bromo-2-(1-methyl isophthalic acid H-tetrazoliums of 3--5-yl)-2-propylene (1.95 grams, 0.005 mole) (embodiment 15 step D systems) and triphenylphosphine (1.3 grams, 0.005 mole) and hexanaphthene (25 milliliters) three's slurries are heated to backflow.After 30 minutes, reaction mixture becomes transparent solution, presents white precipitate after 1 hour.With this mixture reheat 8 hours, cool to room temperature was collected solid with filtration method, washs solid with ether.At down dry these white powders of vacuum, 50 ℃, obtain 3.0 gram (92%) fusing points and be 254~255 ℃ title compound.
IR(KBr) γ
Maximum: 3450,1600,1500,1425 centimetres
-1
1H NMR(DMSO-d
6)δ:7.92~6.80(m,23H),4.94(6d,2H),3.83(S,3H);
13C NMR(DMSO-d
6)δ:163.53、163.36、160.28、160.87、154.04、153.89、152.76、135.11、134.79、134.16、133.68、133.54、130.53、130.45、130.35、130.21、130.07、118.02、116.89、116.18、115.89、115.62、115.32、111.43、111.39、34.22、28.88、28.22。
Analyze:
C
35H
28BrF
2N
4The calculated value of P: C, 64.31; H, 4.32; N, 8.57;
Measured value: C, 64.02; H, 4.37; N, 8.89.
Claims (35)
1, a kind of formula is
Basic cis (4R, 6S) type compound is in the formula: R
7And R
8Hydrogen, C respectively do for oneself
1-6Alkyl or by 1 or 2 C
1-4Phenyl, halogen, C that alkyl replaces arbitrarily
1-4Alkoxyl group or trifluoromethyl; R
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, become cyclopentyl, cyclohexyl or suberyl; With n be 0 or 1.
2, the described compound of claim 1, wherein: R
7And R
8C respectively does for oneself
1-6Alkyl or phenyl; N is 0; And R
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl.
3, the described compound of claim 2, wherein: R
7Be phenyl, R
8Be hydrogen, n is 0; R
9And R
10It respectively is methyl.
4, the described compound of claim 1, wherein: R
7And R
8C respectively does for oneself
1-4Alkyl or phenyl; N is 1; R
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl.
5, the described compound of claim 4, wherein: R
7Be methyl; N is 1; R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl.
7, the described compound of claim 6, wherein: R
9And R
10It respectively is methyl; And R
12Be hydrogen, C
1-4Alkyl or metallic cation.
8, the described compound of claim 7, R wherein
12Be hydrogen.
9, the described compound of claim 7, wherein R
12Be metallic cation, wherein this metallic cation is a lithium cation.
10, the described compound of claim 6, wherein: R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; And R
12Be hydrogen, C
1-4Alkyl or metallic cation.
11, the described compound of claim 10, R wherein
12Be hydrogen.
12, the described compound of claim 10, wherein R
12Be metallic cation, this metallic cation is a lithium cation.
13, having formula is
Basic cis-compound, wherein: R
1And R
4Hydrogen, halogen, C respectively do for oneself
14Alkyl, C
1-4Alkoxyl group or trifluoromethyl; R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1-4Alkyl or C
1-4Alkoxyl group; R
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them, be cyclopentyl, cyclohexyl or suberyl; R
12Be hydrogen, C
1-4Alkyl or metallic cation.
15, the described compound of claim 14, wherein: R
9R
10It respectively is methyl; R
12Be hydrogen, C
14Alkyl or metallic cation.
16, the described compound of claim 15, R wherein
12Be hydrogen.
17, the described compound of claim 14, wherein: R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; R
12Be hydrogen, C
1-4Alkyl or metallic cation.
18, the described compound of claim 17, R wherein
12Be hydrogen.
19, having formula is
Basic cis (4R, the 6S) claim 13 of type compound is in the formula: R
1And R
4Hydrogen, halogen, C respectively do for oneself
1-4Alkyl, C
1-4Alkoxyl group or trifluoromethyl, R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1-4Alkyl or C
1-4Alkoxyl group; R
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10With the carbon atom that is connected them, be cyclopentyl, cyclohexyl and suberyl; R
12Be hydrogen, C
1-4Alkyl or metallic cation.
21, the compound described in the claim 20, wherein: R
9And R
10It respectively is methyl; R
12Be hydrogen, C
1-4Alkyl or metallic cation.
22, the compound described in the claim 21, wherein R
12Be hydrogen.
23, the compound described in the claim 20, wherein: R
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl; R
12Be hydrogen, C
1-4Alkyl or metallic cation.
24, the described compound of claim 23, wherein R
12Be hydrogen.
25, a kind of preparation formula is basic cis (4R, 6S) the method method of type aldehyde of III b.R in the formula
9And R
10Respectively be C
1-4Alkyl,
Or R
9And R
10Lump together with the carbon atom that is connected them and to be cyclopentyl, cyclohexyl and suberyl, R
12Be hydrogen, C
1-4Alkyl or metallic cation; The step that this method comprises has:
(a) make the ester hydrolysis of formula VII, with the compound of production VIII; R in the formula VII
7With
R
8The hydrogen of respectively doing for oneself, C
1-6Alkyl or by 1 or 2 C
1-4Phenyl, halogen, C that alkyl replaces arbitrarily
1-4Alkoxyl group or trifluoromethyl, R
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lumping together with the carbon atom that is connected them becomes cyclopentyl, cyclohexyl or suberyl, and n is 0 or 1, and R
11Be the hydrolysis ester group; R in the formula VIII
7, R
8, R
9, R
10With the definition of n with above-mentioned;
(b) acid of formula VIII is taken apart, with the basic cis of production IX (4R, 6S)
The type compound, R in the formula
7, R
8, R
9, R
10With the definition of n with above-mentioned; With
(c) make the acid oxidase of formula IX, with the basic cis of production III b (4R,
6S) allusion quotation compound, R in the formula
9, R
10And R
12Definition with above-mentioned.
26, the described method of a kind of claim 25, R wherein
9And R
10It respectively is methyl.
27, the described method of a kind of claim 25, R wherein
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl.
28, the described method of a kind of claim 25, wherein R
7Be phenyl, R
8Be that hydrogen and n are 0.
29, the described method of a kind of claim 25, wherein R
7Be methyl, R
8Be that hydrogen and n are 1.
30, a kind of preparation formula is
Trans substantially (4R, the 6S) method of type compound, R in the formula
1And R
4Hydrogen, halogen, C respectively do for oneself
1-4Alkyl, C
1-4Alkoxyl group or trifluoromethyl, R
2, R
3, R
5And R
6Hydrogen, halogen, C respectively do for oneself
1-4Alkyl or C
1-4Alkoxyl group; The step that this method comprises has:
(a) make formula X compound and the basic cis of formula III b (4R, 6S)
The reaction of type compound is with the basic cis of production XII (4R, 6S) type compound;
R in the formula X
1, R
2, R
3, R
4, R
5And R
6Definition with above-mentioned and Z be
, R in the formula
13Be C
14Alkyl, R
14For not by or by 1 or 2 C
14The phenyl that alkyl or chlorine substituent replace, X is bromo, chloro or iodo; Or R among the III b
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them and to be cyclopentyl, cyclohexyl and suberyl, R
12Be hydrogen, C
14Alkyl or metallic cation base; R in the formula XII
1, R
2, R
3, R
4, R
5, R
6, R
9, R
10And R
12Definition with above-mentioned;
(b) make formula XII compound and acid-respons, with production I b compound, R in the formula
1, R
2, R
3, R
4, R
5, R
6And R
12Definition with above-mentioned; With
(c) make R in the formula I a(formula
12Be hydrogen) the compound cyclisation, with production be
Trans substantially (4R, 6S) type compound, the R in the formula
1, R
2, R
3, R
4, R
5And R
6Definition with above-mentioned.
31, the described preparation formula of a kind of claim 30 is
Trans substantially (step that this method comprises has for 4R, the 6S) method of type compound:
(a) make formula X a compound and the basic cis of formula III b (4R, 6S)
The type combination reaction, with the basic cis of production XII a (4R, 6S)
The type compound; Z is among the formula X a
Or
, R wherein
13Be C
14Alkyl, R
14For not by or by 1 or 2 C
1-4The phenyl that alkyl or chlorine substituent replace, X is bromo, chloro or iodo; R among the formula III b
9And R
10Respectively be C
1-4Alkyl, or R
9And R
10Lump together with the carbon atom that is connected them and to be cyclopentyl, cyclohexyl or suberyl, R
12Be hydrogen, C
1-4Alkyl or metallic cation; R among the formula XII a
9, R
10And R
12Definition with above-mentioned;
(b) make formula XII a compound and acid-respons, with production formula I c compound, R in the formula
12Definition with above-mentioned;
(c) make wherein R of formula I a(
12Be hydrogen) the compound cyclisation, with the production formula be
Trans substantially (4R, 6S) type compound.
32, the described method of a kind of claim 31, R wherein
9And R
10It respectively is methyl.
33, the described method of a kind of claim 31, R wherein
9And R
10Lump together with the carbon atom that is connected them, be cyclohexyl.
34, the described method of a kind of claim 31, Z wherein is
, R wherein
14Be phenyl, X is a bromo.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US156,865 | 1988-02-18 | ||
US07/156,865 US4824959A (en) | 1988-02-18 | 1988-02-18 | Intermediates for antihypercholesterolemic tetrazole compounds |
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CN1036013A true CN1036013A (en) | 1989-10-04 |
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Family
ID=22561419
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US (1) | US4824959A (en) |
JP (2) | JP2871707B2 (en) |
KR (1) | KR970002233B1 (en) |
CN (1) | CN1025619C (en) |
AT (1) | AT401057B (en) |
AU (1) | AU621586B2 (en) |
BE (1) | BE1002136A5 (en) |
CA (1) | CA1340430C (en) |
CH (1) | CH680792A5 (en) |
CY (1) | CY1874A (en) |
DD (4) | DD285602A5 (en) |
DE (1) | DE3904899A1 (en) |
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EG (1) | EG19217A (en) |
ES (1) | ES2017810A6 (en) |
FI (1) | FI890725A (en) |
FR (1) | FR2630112B1 (en) |
GB (1) | GB2216121B (en) |
GR (1) | GR1000664B (en) |
HK (3) | HK129295A (en) |
HU (2) | HU204045B (en) |
IE (1) | IE65090B1 (en) |
IT (1) | IT1230750B (en) |
LU (1) | LU87456A1 (en) |
MY (1) | MY106279A (en) |
NL (1) | NL8900397A (en) |
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NZ (1) | NZ227935A (en) |
PT (1) | PT89748B (en) |
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CN104303915A (en) * | 2014-08-25 | 2015-01-28 | 李世峰 | Water floating type seedling cultivation technology for mechanically transplanted rice |
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DE3741509A1 (en) * | 1987-12-08 | 1989-06-22 | Hoechst Ag | METHOD FOR PRODUCING OPTICALLY ACTIVE 3-DESMETHYLMEVALONIC ACID DERIVATIVES AND INTERMEDIATE PRODUCTS |
GB2244705B (en) * | 1988-02-18 | 1992-07-15 | Bristol Myers Co | Preparation of antihypercholesterolemic tetrazole compounds and intermediates thereof |
US5010205A (en) * | 1988-08-23 | 1991-04-23 | Bristol-Myers Company | Antihypercholesterolemic tetrazol-1-yl intermediates |
US4870187A (en) * | 1988-08-23 | 1989-09-26 | Bristol-Myers Company | Antihypercholesterolemic tetrazol-1-yl compounds |
DE4128345C1 (en) * | 1991-08-27 | 1993-06-09 | Hoechst Ag, 6230 Frankfurt, De | 3R,5S 3,5,6-tri:hydroxy-hexanoic acid isopropylidene ketal derivs. prepn. - from 7-benzyl:oxy 4,6-di:hydroxy:heptene by multistage process |
US5278313A (en) * | 1992-03-27 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors |
US5284957A (en) * | 1992-09-03 | 1994-02-08 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
CA2137049A1 (en) * | 1993-12-15 | 1995-06-16 | John K. Thottathil | Amino acid salts of and methods for preparing antihypercholesterolemic tetrazole compounds |
DE10147030A1 (en) * | 2001-09-04 | 2003-03-27 | Forschungszentrum Juelich Gmbh | Separation of diastereomer mixture of syn- and anti-1,3-diol acetal, giving products useful e.g. as drug intermediates, comprises selective partial hydrolysis to give syn-acetal and anti-diol |
US20050272808A1 (en) * | 2004-05-11 | 2005-12-08 | Nadav Zamir | Compositions and methods for the treatment of hypertension |
WO2005107739A1 (en) * | 2004-05-11 | 2005-11-17 | Darley Pharmaceuticals Ltd. | Spiroderivatives for the treatment of hypertension |
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JPS58225085A (en) * | 1982-06-24 | 1983-12-27 | Nippon Kayaku Co Ltd | Acetal glycol diacrylate and its preparation |
US4808621A (en) * | 1986-07-07 | 1989-02-28 | Warner-Lambert Company | Trans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)-ethyl]- or ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis |
US4837205A (en) * | 1986-09-02 | 1989-06-06 | Merck & Co., Inc. | Prodrugs of antihypercholesterolemic compounds |
US4897490A (en) * | 1987-02-25 | 1990-01-30 | Bristol-Meyers Company | Antihypercholesterolemic tetrazole compounds |
US4751229A (en) * | 1987-07-09 | 1988-06-14 | Warner-Lambert Company | Treating fungal infections with substituted-(6-(tetrahydro-4-hydroxy-2-oxo-2H-pyran-2-yl)ethyl)- or ethenyl)pyrazoles |
DE3807929A1 (en) * | 1988-03-10 | 1989-09-28 | Basf Ag | METHOD FOR THE PRODUCTION OF RELEASE STANDARDS |
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- 1989-02-17 DE DE3904899A patent/DE3904899A1/en not_active Ceased
- 1989-02-17 DD DD89334039A patent/DD285600A5/en unknown
- 1989-02-17 DD DD89334043A patent/DD285603A5/en unknown
- 1989-02-17 KR KR1019890001890A patent/KR970002233B1/en not_active IP Right Cessation
- 1989-02-17 LU LU87456A patent/LU87456A1/en unknown
- 1989-02-17 DD DD89325844A patent/DD283618A5/en unknown
- 1989-02-17 SE SE8900565A patent/SE503179C2/en not_active IP Right Cessation
- 1989-02-17 AT AT0036189A patent/AT401057B/en not_active IP Right Cessation
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1993
- 1993-02-23 SE SE9300595A patent/SE9300595A0/en not_active Application Discontinuation
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1995
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- 1995-08-17 HK HK129395A patent/HK129395A/en not_active IP Right Cessation
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1996
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1998
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104303915A (en) * | 2014-08-25 | 2015-01-28 | 李世峰 | Water floating type seedling cultivation technology for mechanically transplanted rice |
CN104303915B (en) * | 2014-08-25 | 2016-05-25 | 李世峰 | A kind of machine-transplanted rice water floating type seedling-cultivation technique |
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